Conjugate Addition Reactions Using Bifunctional Cinchona-Alkaloid-Based Catalysts

ABSTRACT

One aspect of the present invention relates to quinine-based and quinidine-based catalysts. Another aspect of the present invention relates to a method of preparing a chiral, non-racemic compound from a prochiral electron-deficient alkene, comprising the step of: reacting a prochiral electron-deficient alkene with a nucleophile in the presence of a catalyst; thereby producing a chiral, non-racemic compound; wherein said catalyst is a derivatized quinine or quinidine.

RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 13/133,438, now U.S. Pat. No. 8,722,891, which is a §371 nationalstage application based on Patent Cooperation Treaty Application serialnumber PCT/US2009/066990, filed Dec. 7, 2009; which claims the benefitof priority to U.S. Provisional Patent Application Ser. No. 61/120,612,filed Dec. 8, 2008.

GOVERNMENT SUPPORT

The invention was made with support provided by the National Institutesof Health (GM-61591); therefore, the government has certain rights inthe invention.

BACKGROUND OF THE INVENTION

The demand for enantiomerically pure compounds has grown rapidly inrecent years. One important use for such chiral, non-racemic compoundsis as intermediates for synthesis in the pharmaceutical industry. Forinstance, it has become increasingly clear that enantiomerically puredrugs have many advantages over racemic drug mixtures. These advantagesinclude the fewer side effects and greater potency often associated withenantiomerically pure compounds.

Traditional methods of organic synthesis were often optimized for theproduction of racemic materials. The production of enantiomerically purematerial has historically been achieved in one of two ways: use ofenantiomerically pure starting materials derived from natural sources(the so-called “chiral pool”); and the resolution of racemic mixtures byclassical techniques. Each of these methods has serious drawbacks,however. The chiral pool is limited to compounds found in nature, soonly certain structures and configurations are readily available.Resolution of racemates, which requires the use of resolving agents, maybe inconvenient and time-consuming.

Enantiomerically pure materials may be obtained by asymmetric conjugateaddition of a nucleophile to an electron-poor alkene. The asymmetricconjugate addition is one of the most powerful bond-forming reactions toconstruct enantioenriched, highly functional carbon skeletons for thetotal synthesis of natural and biologically active compounds. Forreviews see: (a) B. E. Rossiter, N. M. Swingle, Chem. Rev. 1992,771-806; (b) J. Leonard, E. Diez-Barra, S. Merino, Eur. J. Org. Chem.1998, 2051-2061; (c) K. Tomioka, Y Nagaoka, Comprehensive AsymmetricCatalysis (Eds.: E. N. Jacobsen, A Pfaltz, H. Yamamoto), Springer,Berlin, 1999, vol. 3, p. 1105-1120; (d) M. Yamaguci, ComprehensiveAsymmetric Catalysis (Eds.: E. N. Jacobsen, A Pfaltz, H. Yamamoto),Springer, Berlin, 1999, vol. 3, p. 1121-1139; (e) M. P. Sibi, S. Manyem,Tetrahedron 2000, 56, 8033-8061; (f) N. Krause, A. Hoffmann-RoderSynthesis 2001, 171-196. For general reviews on conjugate additions see:(g) P Perlmutter, Conjugate Addition Reactions in Organic Synthesis(Eds.: J. E. Baldwin, P D. Magnus), Pergamon Press, Oxford, 1992; (h) M.E. Jung, Comprehensive Organic Synthesis (Ed.: B. M. Trost), PergamonPress, Oxford, 1991, vol. 4, pp. 1-67. Its strategic importance isevident by considering that a Michael addition can represent theinitiating step of more complex inter- and intramolecular tandemprocesses. For reviews see: (a) L. F Tietze, Chem. Rev. 1996, 96,115-136; (b) R. A. Brunce, Tetrahedron 1995, 48, 13103-13159; (c) L.Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137-170; Angew Chem. Int. EdEngl. 1993, 32, 131-163; (d) G. H. Posner, Chem. Rev. 1986, 86, 831-844.

Among the Michael acceptors, nitroalkenes are very attractive, becausethe nitro group is the most electron-withdrawing group known. N. Ono,The Nitro Group in Organic Synthesis, Wiley-VCH, New York, 2001; D.Seebach, E. W. Colvin, F Lehr, T Weller, Chimia 1979, 33, 1-18. Oftendescribed as a “synthetic chameleon,” the nitro group can serve asmasked functionality to be further transformed after the addition hastaken place. G. Calderari, D. Seebach, Helv. Chim. Acta 1995, 68,1592-1604. The Nef reaction, the nucleophilic displacement, thereduction to amino group, the Myer reaction, and the conversion into anitrile oxide are only examples of the transformations that nitro groupscan undergo. H. W Pinnick, Org. React. 1990, 38, 655-792; J. U. Nef,Justus Liebigs Ann. Chem. 1894, 280, 263-291; R. Tamura, A. Kamimura, N.Ono, Synthesis 1991, 423-434; R. C. Larock, Comprehensive OrganicTransformations, VCH, New York, 1989, pp. 411-415; A. K. Beck, D.Seebach, Chem. Ber. 1991, 124, 2897-2911; R. E. Maeri, J. Heinzer, D.Seebach, Liebigs Ann. 1995, 1193-1215; M. A. Poupart, G. Fazal, S.Goulet, L. T Mar, J. Org. Chem. 1999, 64, 1356-1361; A. G. M. Barrett,C. D. Spilling, Tetrahedron Lett. 1988, 29, 5733-5734; D. H. Lloyd, D.E. Nichols, J. Org. Chem. 1986, 51, 4294-4298; V. Meyer, C. Wurster,Ber. Dtsch. Chem. Ges. 1873, 6, 1168-1172; M. J. Kamlet, L. A. Kaplan,J. C. Dacons, J Org. Chem. 1961, 26, 4371-4375; T. Mukayama, T Hoshino,J. Am. Chem. Soc. 1960, 82, 5339-5342. A number of catalytic syntheticmethods have been developed in recent years, making use of nitroalkeneseven more attractive. A. G. M. Barret, G. G. Graboski, Chem. Rev. 1986,86, 751-762; R. Ballini, R. Castagnani, M. Petrini, J. Org. Chem. 1992,57, 2160-2162; G. Rosini, R. Ballini, M. Petrini, P Sorrenti, Synthesis1985, 515-517.

Conjugate additions of carbon nucleophiles to alkenyl sulfones inparallel to those to nitroalkenes constitute a class of syntheticallyvaluable C—C bond forming reactions. Accordingly, considerable effortshave been devoted to the development of asymmetric conjugate additionsto alkenyl sulfones. Although significant advancements have been made inthe use of chiral auxiliary strategy, the realization of a highlyenantioselective catalytic conjugate additions with alkenyl sulfonesremains elusive. For reviews of enantioselective conjugate additions,see (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033-8061; (b)Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171-196; (c) M. Yamaguchiin Comprehensive Asymmetric Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz,H. Yamamoto), Springer, Heidelberg, 2003, Suppl. 1, Supplement to chap.31.2, p. 151. (a) Pinheiro, S.; Guingant, A.; Desmaële, D.; d'Angelo, J.Tetrahedron: Asymmetry 1992, 3, 1003; (b) d'Angelo, J.; Revial, G.Tetrahedron: Asymmetry 1991, 2, 199. Lin, Y.; Ali, B. E.; Alper, H. J.Am. Chem. Soc. 2001, 123, 7719. For a conjugate addition of chiral1-aminopyrrolidine to alkenyl sulfones see: Enders, D.; Müller, S. F.;Raabe, G.; Runsink, J. Eur. J. Org. Chem. 2000, 879. (a) Reddick, J. J.;Cheng, J.; Roush, W. R. Org. Lett. 2003, 5, 1967; (b) Sanki, A. K.;Suresh, C. G.; Falgune, U. D.; Pathak, T. Org. Lett. 2003, 5, 1285; (c)Ravindran, B.; Sakthivel, K.; Suresh, C. G.; Pathak, T. J. Org. Chem.2000, 65, 2637; (d) Farthing, C.; Marsden, S. P. Tetrahedron Lett. 2000,41, 4235-4238; (e) Hirama, M.; Hioki, H.; Itô, S.; Kabuto, C.Tetrahedron Lett. 1988, 29, 3121. For intramolecular Michael addition toalkenyl sulfones see: Carretero, J. C.; Arrayas, R. G. J. Org. Chem.1998, 63, 2993; for a Rh-catalyzed enantioselective conjugate additionof organoboronic acids to trans-β-substituted vinyl sulfones see:Mauleon, P.; Carretero, J. C. Org. Lett. 2004, 6, 3195.

Additionally, the conjugate addition of carbon nucleophiles to alkenylketones provides a powerful strategy for the creation of all-carbonquaternary stereocenters, due to the accessibility of a wide range ofboth the Michael donors and acceptors and the proven wide utility of the1,4-adducts. Remarkably, in spite of numerous great strides made sincethen in catalytic asymmetric synthesis, this task remains a dauntingchallenge of undiminished synthetic significance. Wynberg, H.; Helder,R. Tetrahedron Letters 1975, 46, 4057-4060. Sawamura, M.; Hamashima, H.;Ito, Y. J. Am. Chem. Soc. 1992, 114, 8295-8296. Sasai, H.; Emori, E.;Arai, T.; Shibasaki, M. Tetrahedron Letters 1996, 37, 5561-5564.Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124,11240-11241. Bella, M.; Jorgensen, A. J. Am. Chem. Soc. 2004, 126,5672-5673. For chiral (salen) A1 complex-catalyzed conjugate addition ofα-phenyl α-cyanoacetate to an acyclic α,β-unsaturated ketones, seeTaylor, M. S.; Zalatan, D. N.; Lerchner, A. M.; Jacobsen, E. N. J. Am.Chem. Soc. 2005, 127, 1313-1317. For a special issue focusing onasymmetric catalysis, see: Proc. Natl. Acad. Sci. USA 2004, 101,5347-5850. (b) For a thematic issue for Enantioselective Catalysis see:(Eds: Bolm, C.; Gladysz, J.) Chem. Rev. 2003, 103, 2761-3400. (c)Comprehensive Asymmetric Catalysis, E. N. Jacobsen, A. Pfaltz, H.Yamamoto Eds, Springer-Verlag, Berlin, 1999, Vol. 1-3. Anenantioselective catalytic conjugate addition of α-substitutedketoesters to vinyl ketones was reported by Shibasaki and coworkers in1994. Sasai, H.; Emori, E.; Arai, T.; Shibasaki, M. Tetrahedron Letters1996, 37, 5561-5564. With a bifunctional chiral La-Na-BINOL complex, theaddition of cyclic and acyclic α-substituted ketoesters to methyl vinylketone (MVK) proceeded in 62-91% ee. More recently, Sodeoka andcoworkers reported a Pd-BINAP complex that afforded 86-93% ee for theconjugate addition of α-substituted ketoesters to methyl and ethyl vinylketones. Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002,124, 11240-11241. These chiral metal complex-mediated reactions, whiledemonstrating substantial scopes with respect to ketoester donors,afforded greater than 90% ee only with MVK as the Michael acceptor.Moreover, performed at −50 to −20° C., a catalyst loading of 5-10 mol %is required for the reaction to reach completion in 15 to 72 hours.Although representing remarkable progresses, these results underscoreboth the urgency and challenge for the development of an operationallysimple, efficient and rapid enantioselective catalytic conjugateaddition of broad substrate scopes for alkenyl ketones.

The present invention relates in part to the catalytic asymmetricsynthesis of chiral compounds from prochiral substrates, such asnitroalkenes, alkenyl sulfones and alkenyl ketones.

Catalytic asymmetric synthesis is providing chemists with new andpowerful tools for the efficient synthesis of complex molecules. Whilemany of the catalytic systems are metal-based and rely on chiral Lewisacid and organometallic redox-based catalysis, increasing numbers ofasymmetric reactions are catalyzed by chiral nucleophiles, building onthe vast assortment of situations in nature in which nucleophiles playpivotal roles. For leading references, see: (a) In ComprehensiveAsymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;Springer: Heidelberg, 1999; (b) In Asymmetric Catalysis in OrganicSynthesis, Noyori, R., Ed.; Wiley: New York, 1994; (c) In AsymmetricSynthesis, 2nd ed.; Ojima, I., Ed.; VCH: New York, 2000; (d) Acc. Chem.Res. 2000, 33, 323. (e) Groger, H.; Wilken, J. Angew. Chem., Int. Ed.2001, 40, 529; (f) Pierre, J.-L. Chem. Soc. Rev. 2000, 29, 251-257. (g)Roberts, B. P. Chem. Soc. Rev. 1999, 28, 25. Chiral amines play acentral role in this expanding area of asymmetric catalysis. Althoughchiral amines have been utilized extensively as chiral ligands, theyhave also shown great promise in catalyzing a broad range of asymmetrictransformations, yielding optically enriched products in highselectivity and yield that may not be accessible through alternativeasymmetric technology. Seyden-Penne, J. Chiral Auxiliaries and Ligandsin Asymmetric Synthesis; Wiley & Sons: New York, 1995.

Historically, the cinchona alkaloids were the first chiral amines to beused in asymmetric catalysis, most notably in the pioneering work ofPracejus from the 1960's on disubstituted ketene alcoholysis. Cinchonaalkaloids also possess a rich and colorful history that is rooted innatural products and pharmaceutical chemistry. Turner, R. B.; Woodward,R. B. In In the Alkaloids; Manske, R. H. F.; Holmes, H. L., Eds.;Academic Press: New York, 1953; Vol. 3, p 24; Verpoorte, R.; Schripsema,J.; Van der Leer, T. In In the Alkaloids. Chemistry and Pharmacology,Brossi, A., Ed.; Academic Press: New York, 1988; Vol. 34; Michael, J. P.In The Quinoline Alkaloids, In Rodd's Chemistry of Carbon Compounds, 2nded.; Sainsbury, M., Ed.; Elsevier: Amsterdam, 1998; 2nd suppl., part Fand G, vol 4; 432. They are isolated en masse by extracting the bark ofthe cinchona tree, which is native to tropical regions. Outside oforganic chemistry, the cinchona alkaloids have found wide use as foodflavorings (for example as the bitter principle of tonic water) and inthe treatment of malaria. Fletcher, D. C. J. Am. Med. Assoc. 1976, 236,305; Mturi, N.; Musumba, C. O.; Wamula, B. M.; Ogutu, B. R.; Newton, C.R. J. C. CNS Drugs 2003, 17, 153. Additionally, their roles as ligands,chromatographic selectors, and NMR discriminating agents have beenexamined extensively over the past thirty years. Several reviews havebeen published on the catalytic chemistry of cinchona alkaloids over thepast four decades. Pracejus, H. Forschr. Chem. Forsch. 1967, 8, 493;Morrison, J. D.; Mosher, H. S. Asymmetric Organic Reactions; PrenticeHall: Englewood Cliffs, 1971; Wynberg, H. Top. Stereochem. 1986, 16, 87;Kacprzak, K.; Gawronski, J. Synthesis 2001, 7, 961.

These reactions appear to be broadly applicable to both research andindustrial scale asymmetric synthesis of a wide variety of importantchiral building blocks, such as hemi-esters, α-amino acids and α-hydroxyacids. Commercially available modified dimeric cinchona alkaloids(DHQD)₂AQN, (DHQ)₂AQN (see FIG. 1), have been identified recently byDeng and coworkers as enantioselective and recyclable catalysts forenantioselective alcoholyses of cyclic anhydrides. However, commerciallyavailable (DHQD)₂AQN is expensive. For example, the commercial price(Aldrich Chemical Company) for a mole of (DHQD)₂AQN is more than$100,000.00. Furthermore, the dimeric catalyst is not available in largequantity (e.g., in kilogram quantity). Therefore, stereoselectivereactions using dimeric catalysts are not practical on a relativelylarge scale (>0.1 mol). Consequently, the development of a newgeneration of monomeric catalysts that is comparably effective to(DHQD)₂AQN, but substantially less costly to produce, is of significantpractical value.

Chiral metal and organic catalysts that possess both an acidic and abasic/nucleophilic structural moiety constitute an increasingly powerfulplatform for the development of asymmetric catalysis. The design anddevelopment of such bifunctional chiral catalysts that are efficient yeteasily accessible continues to be a major challenge. Wynberg andcoworkers demonstrated that natural cinchona alkaloids, via their C9-OHand amine groups, served as bifunctional chiral organic catalysts byactivating the nucleophile and electrophile, respectively, forenantioselective reactions. Wynberg, H., Hiemstra, H., J. Am. Chem.Soc., 1981, 103, 417. However, the enantioselectivity of variousreactions catalyzed by natural cinchona alkaloids as chiral organiccatalysts was usually modest. Hatakeyama and coworkers recently reporteda rigid modified cinchona alkaloid that is readily accessible fromquinidine. Hatakeyama, S. et al., J. Am. Chem. Soc., 1999, 121, 10219;Hatakeyama, S., Organic Lett., 2003, 5, 3103. The catalyst was found tobe efficient for an enantioselective Morita-Baylis-Hillman (MBH)reaction. Both the C6′-OH and the amine groups are believed to beinvolved in the stabilization of the transition state of theenantioselective MBH reaction.

Remarkably, we have developed readily accessible bifunctional organiccatalysts derived from either quinidine or quinine that can be used inhighly enantioselective C—C bond forming reactions.

SUMMARY OF THE INVENTION

One aspect of the present invention relates generally to quinine- andquinidine-based catalysts. In certain embodiments, the quinine- andquinidine-based catalysts contain a hydrogen bond donating group at the6′ position. In certain embodiments, the quinine- and quinidine-basedcatalysts contain a hydroxy group at the 6′ position. In certainembodiments, the quinine- and quinidine-based catalysts contain anO-aralkyl group or O-heteroaralkyl group at the C9 position.

Another aspect of the present invention relates to a compoundrepresented by formula I:

wherein, independently for each occurrence:

R represents substituted or unsubstituted aralkyl or heteroaralkyl;

R₁ represents alkyl or alkenyl;

R₂ and R₃ represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl,heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy,amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine,carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether,ketone, aldehyde, or ester;

n is an integer from 0 to 5 inclusive;

m is an integer from 0 to 8 inclusive; and

R₄ represents OR₅, wherein R₅ is H or alkyl.

Yet another aspect of the present invention relates to a compoundrepresented by formula II:

wherein, independently for each occurrence:

R represents substituted or unsubstituted aralkyl or heteroaralkyl;

R₁ represents alkyl or alkenyl;

R₂ and R₃ represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl,heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy,amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine,carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether,ketone, aldehyde, or ester;

n is an integer from 0 to 5 inclusive;

m is an integer from 0 to 8 inclusive; and

R₄ represents OR₅, wherein R₅ is H or alkyl.

The invention also relates to a method of preparing a chiral,non-racemic compound from a prochiral electron-deficient alkene,comprising the step of:

reacting a prochiral electron-deficient alkene with a nucleophile in thepresence of a catalyst; thereby producing a chiral, non-racemiccompound; wherein said catalyst is represented by formula I or II.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 depicts the structure and nomenclature of severalcinchona-alkaloid-based catalysts.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For convenience, certain terms employed in the specification, examples,and appended claims are collected here.

The term “nucleophile” is recognized in the art, and as used hereinmeans a chemical moiety having a reactive pair of electrons. Examples ofnucleophiles include uncharged compounds such as water, amines,mercaptans and alcohols, and charged moieties such as alkoxides,thiolates, carbanions, and a variety of organic and inorganic anions.Illustrative anionic nucleophiles include simple anions such ashydroxide, azide, cyanide, thiocyanate, acetate, formate orchloroformate, and bisulfite. Organometallic reagents such asorganocuprates, organozincs, organolithiums, Grignard reagents,enolates, acetylides, and the like may, under appropriate reactionconditions, be suitable nucleophiles. Hydride may also be a suitablenucleophile when reduction of the substrate is desired.

The term “electrophile” is art-recognized and refers to chemicalmoieties which can accept a pair of electrons from a nucleophile asdefined above. Electrophiles useful in the method of the presentinvention include cyclic compounds such as epoxides, aziridines,episulfides, cyclic sulfates, carbonates, lactones, lactams and thelike. Non-cyclic electrophiles include sulfates, sulfonates (e.g.,tosylates), chlorides, bromides, iodides, and the like

The terms “electrophilic atom”, “electrophilic center” and “reactivecenter” as used herein refer to the atom of the substrate which isattacked by, and forms a new bond to, the nucleophile. In most (but notall) cases, this will also be the atom from which the leaving groupdeparts.

The term “electron-withdrawing group” is recognized in the art and asused herein means a functionality which draws electrons to itself morethan a hydrogen atom would at the same position. Exemplaryelectron-withdrawing groups include nitro, ketone, aldehyde, sulfonyl,trifluoromethyl, —CN, chloride, and the like. The term“electron-donating group”, as used herein, means a functionality whichdraws electrons to itself less than a hydrogen atom would at the sameposition. Exemplary electron-donating groups include amino, methoxy, andthe like.

The term “Bronsted base” is art-recognized and refers to an uncharged orcharged atom or molecule, e.g., an oxide, amine, alkoxide, or carbonate,that is a proton acceptor.

The terms “Lewis base” and “Lewis basic” are recognized in the art, andrefer to a chemical moiety capable of donating a pair of electrons undercertain reaction conditions. Examples of Lewis basic moieties includeuncharged compounds such as alcohols, thiols, olefins, and amines, andcharged moieties such as alkoxides, thiolates, carbanions, and a varietyof other organic anions.

The terms “Lewis acid” and “Lewis acidic” are art-recognized and referto chemical moieties which can accept a pair of electrons from a Lewisbase.

The term “meso compound” is recognized in the art and means a chemicalcompound which has at least two chiral centers but is achiral due to aninternal plane, or point, of symmetry.

The term “chiral” refers to molecules which have the property ofnon-superimposability on their mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner. A “prochiral molecule” is an achiral molecule which hasthe potential to be converted to a chiral molecule in a particularprocess.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement oftheir atoms or groups in space. In particular, the term “enantiomers”refers to two stereoisomers of a compound which are non-superimposablemirror images of one another. The term “diastereomers”, on the otherhand, refers to the relationship between a pair of stereoisomers thatcomprise two or more asymmetric centers and are not mirror images of oneanother.

Furthermore, a “stereoselective process” is one which produces aparticular stereoisomer of a reaction product in preference to otherpossible stereoisomers of that product. An “enantioselective process” isone which favors production of one of the two possible enantiomers of areaction product. The subject method is said to produce a“stereoselectively-enriched” product (e.g., enantioselectively-enrichedor diastereoselectively-enriched) when the yield of a particularstereoisomer of the product is greater by a statistically significantamount relative to the yield of that stereoisomer resulting from thesame reaction run in the absence of a chiral catalyst. For example, anenantioselective reaction catalyzed by one of the subject chiralcatalysts will yield an ee for a particular enantiomer that is largerthan the ee of the reaction lacking the chiral catalyst.

The term “regioisomers” refers to compounds which have the samemolecular formula but differ in the connectivity of the atoms.Accordingly, a “regioselective process” is one which favors theproduction of a particular regioisomer over others, e.g., the reactionproduces a statistically significant preponderance of a certainregioisomer.

The term “reaction product” means a compound which results from thereaction of a nucleophile and a substrate. In general, the term“reaction product” will be used herein to refer to a stable, isolablecompound, and not to unstable intermediates or transition states.

The term “substrate” is intended to mean a chemical compound which canreact with a nucleophile, or with a ring-expansion reagent, according tothe present invention, to yield at least one product having astereogenic center.

The term “catalytic amount” is recognized in the art and means asubstoichiometric amount relative to a reactant. As used herein, acatalytic amount means from 0.0001 to 90 mole percent relative to areactant, more preferably from 0.001 to 50 mole percent, still morepreferably from 0.01 to 10 mole percent, and even more preferably from0.1 to 5 mole percent relative to a reactant.

As discussed more fully below, the reactions contemplated in the presentinvention include reactions which are enantioselective,diastereoselective, and/or regioselective. An enantioselective reactionis a reaction which converts an achiral reactant to a chiral productenriched in one enantiomer. Enantioselectivity is generally quantifiedas “enantiomeric excess” (ee) defined as follows:

% Enantiomeric Excess A(ee)=(% Enantiomer A)−(% Enantiomer B)

where A and B are the enantiomers formed. Additional terms that are usedin conjunction with enatioselectivity include “optical purity” or“optical activity”. An enantioselective reaction yields a product withan ee greater than zero. Preferred enantioselective reactions yield aproduct with an ee greater than 20%, more preferably greater than 50%,even more preferably greater than 70%, and most preferably greater than80%.

A diastereoselective reaction converts a chiral reactant (which may beracemic or enantiomerically pure) to a product enriched in onediastereomer. If the chiral reactant is racemic, in the presence of achiral non-racemic reagent or catalyst, one reactant enantiomer mayreact more slowly than the other. This class of reaction is termed akinetic resolution, wherein the reactant enantiomers are resolved bydifferential reaction rate to yield both enantiomerically-enrichedproduct and enantiomerically-enriched unreacted substrate. Kineticresolution is usually achieved by the use of sufficient reagent to reactwith only one reactant enantiomer (i.e., one-half mole of reagent permole of racemic substrate). Examples of catalytic reactions which havebeen used for kinetic resolution of racemic reactants include theSharpless epoxidation and the Noyori hydrogenation.

A regioselective reaction is a reaction which occurs preferentially atone reactive center rather than another non-identical reactive center.For example, a regioselective reaction of an unsymmetrically substitutedepoxide substrate would involve preferential reaction at one of the twoepoxide ring carbons.

The term “non-racemic” with respect to the chiral catalyst, means apreparation of catalyst having greater than 50% of a given enantiomer,more preferably at least 75%. “Substantially non-racemic” refers topreparations of the catalyst which have greater than 90% ee for a givenenantiomer of the catalyst, more preferably greater than 95% ee.

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, branched-chain alkyl groups,cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, andcycloalkyl substituted alkyl groups. In preferred embodiments, astraight chain or branched chain alkyl has 30 or fewer carbon atoms inits backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ for branchedchain), and more preferably 20 of fewer. Likewise, preferred cycloalkylshave from 4-10 carbon atoms in their ring structure, and more preferablyhave 5, 6 or 7 carbons in the ring structure.

Unless the number of carbons is otherwise specified, “lower alkyl” asused herein means an alkyl group, as defined above, but having from oneto ten carbons, more preferably from one to six carbon atoms in itsbackbone structure. Likewise, “lower alkenyl” and “lower alkynyl” havesimilar chain lengths.

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but which contain at least one double or triple carbon-carbonbond, respectively.

As used herein, the term “amino” means —NH₂; the term “nitro” means—NO₂; the term “halogen” designates —F, —Cl, —Br or —I; the term “thiol”means —SH; the term “hydroxyl” means —OH; the term “sulfonyl” means—SO₂—; and the term “organometallic” refers to a metallic atom (such asmercury, zinc, lead, magnesium or lithium) or a metalloid (such assilicon, arsenic or selenium) which is bonded directly to a carbon atom,such as a diphenylmethylsilyl group.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety that can berepresented by the general formula:

wherein R₉, R₁₀ and R′₁₀ each independently represent a group permittedby the rules of valence.

The term “acylamino” is art-recognized and refers to a moiety that canbe represented by the general formula:

wherein R₉ is as defined above, and R′₁₁ represents a hydrogen, analkyl, an alkenyl or —(CH₂)_(m)—R₈, where m and R₈ are as defined above.

The term “amido” is art-recognized as an amino-substituted carbonyl andincludes a moiety that can be represented by the general formula:

wherein R₉, R₁₀ are as defined above. Preferred embodiments of the amidewill not include imides which may be unstable.

The term “alkylthio” refers to an alkyl group, as defined above, havinga sulfur radical attached thereto. In preferred embodiments, the“alkylthio” moiety is represented by one of —S-alkyl, —S-alkenyl,—S-alkynyl, and —S—(CH₂)_(m)—R₈, wherein m and R₈ are defined above.Representative alkylthio groups include methylthio, ethyl thio, and thelike.

The term “carbonyl” is art-recognized and includes such moieties as canbe represented by the general formula:

wherein X is a bond or represents an oxygen or a sulfur, and R₁₁represents a hydrogen, an alkyl, an alkenyl, —(CH₂)_(m)—R₈ or apharmaceutically acceptable salt, R′₁₁ represents a hydrogen, an alkyl,an alkenyl or —(CH₂)_(m)—R₈, where m and R₈ are as defined above. WhereX is oxygen and R₁₁ or R′₁₁ is not hydrogen, the formula represents an“ester”. Where X is oxygen, and R₁₁ is as defined above, the moiety isreferred to herein as a carboxyl group, and particularly when R₁₁ ishydrogen, the formula represents a “carboxylic acid”. Where X is oxygen,and R′₁₁ is hydrogen, the formula represents a “formate”. In general,where the oxygen atom of the above formula is replaced by sulfur, theformula represents a “thiolcarbonyl” group. Where X is sulfur and R₁₁ orR′₁₁ is not hydrogen, the formula represents a “thiolester.” Where X issulfur and R₁₁ is hydrogen, the formula represents a “thiolcarboxylicacid.” Where X is sulfur and R₁₁′ is hydrogen, the formula represents a“thiolformate.” On the other hand, where X is a bond, and R₁₁ is nothydrogen, the above formula represents a “ketone” group. Where X is abond, and R₁₁ is hydrogen, the above formula represents an “aldehyde”group.

The terms “alkoxyl” or “alkoxy” as used herein refers to an alkyl group,as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as can berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(CH₂)_(m)—R₈,where m and R₈ are described above.

The term “sulfonate” is art-recognized and includes a moiety that can berepresented by the general formula:

in which R₄₁ is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The term “sulfonylamino” is art-recognized and includes a moiety thatcan be represented by the general formula:

The term “sulfamoyl” is art-recognized and includes a moiety that can berepresented by the general formula:

The term “sulfonyl”, as used herein, refers to a moiety that can berepresented by the general formula:

in which R₄₄ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

The term “sulfoxido” as used herein, refers to a moiety that can berepresented by the general formula:

in which R₄₄ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.

The term “sulfate”, as used herein, means a sulfonyl group, as definedabove, attached to two hydroxy or alkoxy groups. Thus, in a preferredembodiment, a sulfate has the structure:

in which R₄₀ and R₄₁ are independently absent, a hydrogen, an alkyl, oran aryl. Furthermore, R₄₀ and R₄₁, taken together with the sulfonylgroup and the oxygen atoms to which they are attached, may form a ringstructure having from 5 to 10 members.

Analogous substitutions can be made to alkenyl and alkynyl groups toproduce, for example, alkenylamines, alkynylamines, alkenylamides,alkynylamides, alkenylimines, alkynylimines, thioalkenyls, thioalkynyls,carbonyl-substituted alkenyls or alkynyls, alkenoxyls, alkynoxyls,metalloalkenyls and metalloalkynyls.

The term “aryl” as used herein includes 4-, 5-, 6- and 7-memberedsingle-ring aromatic groups which may include from zero to fourheteroatoms, for example, benzene, naphthalene, anthracene,phenanthrene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole,thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine andpyrimidine, and the like. Those aryl groups having heteroatoms in thering structure may also be referred to as “heteroaryl”. The aromaticring can be substituted at one or more ring positions with suchsubstituents as described above, as for example, halogens, alkyls,alkenyls, alkynyls, hydroxyl, amino, nitro, thiol amines, imines,amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers,thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or—(CH₂)_(m)—R₇, —CF₃, —CN, or the like.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group (as defined above). For example, a benzyl group(—CH₂Ph) is an aralkyl group.

The terms “heterocycle” or “heterocyclic group” refer to 4 to10-membered ring structures, more preferably 5 to 7 membered rings,which ring structures include one to four heteroatoms. Heterocyclicgroups include pyrrolidine, oxolane, thiolane, imidazole, oxazole,piperidine, piperazine, morpholine. The heterocyclic ring can besubstituted at one or more positions with such substituents as describedabove, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl,amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines,carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls,selenoethers, ketones, aldehydes, esters, or —(CH₂)_(m)—R₇, —CF₃, —CN,or the like.

The terms “polycycle” or “polycyclic group” refer to two or more cyclicrings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/orheterocycles) in which two or more carbons are common to two adjoiningrings, e.g., the rings are “fused rings”. Rings that are joined throughnon-adjacent atoms are termed “bridged” rings. Each of the rings of thepolycycle can be substituted with such substituents as described above,as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino,nitro, thiol, amines, imines, amides, phosphonates, phosphines,carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls,selenoethers, ketones, aldehydes, esters, or —(CH₂)_(m)—R₇, —CF₃, —CN,or the like.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen,sulfur, phosphorus and selenium.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstitutedbenzenes, respectively. For example, the names 1,2-dimethylbenzene andortho-dimethylbenzene are synonymous.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized andrefer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl,and nonafluorobutanesulfonyl groups, respectively. The terms triflate,tosylate, mesylate, and nonaflate are art-recognized and refer totrifluoromethanesulfonate ester, p-toluenesulfonate ester,methanesulfonate ester, and nonafluorobutanesulfonate ester functionalgroups and molecules that contain said groups, respectively.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms, represent methyl,ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled Standard List of Abbreviations. The abbreviationscontained in said list, and all abbreviations utilized by organicchemists of ordinary skill in the art are hereby incorporated byreference.

The phrase “protecting group” as used herein means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York,1991).

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described hereinabove. The permissible substituentscan be one or more and the same or different for appropriate organiccompounds. For purposes of this invention, the heteroatoms such asnitrogen may have hydrogen substituents and/or any permissiblesubstituents of organic compounds described herein which satisfy thevalencies of the heteroatoms. This invention is not intended to belimited in any manner by the permissible substituents of organiccompounds.

The term “1-adamantyl” is art-recognized and includes a moietyrepresented by the formula:

The term “(−)-menthyl” is art-recognized and includes a moietyrepresented by the formula:

The term “(+)-menthyl” is art-recognized and includes a moietyrepresented by the formula:

The term “isobornyl” is art-recognized and includes a moiety representedby the formula:

The term “isopinocamphyl” is art-recognized and includes a moietyrepresented by the formula:

The term “(+)-fenchyl” is art-recognized and includes a moietyrepresented by the formula:

The abbreviation “QD” represents a moiety according to the followingformula:

The term “Q” represents a moiety according to the following formula:

Catalysts of the Invention

The catalysts employed in the subject methods are non-racemic chiralamines which present an asymmetric environment, causing stereochemicaldiscrimination between two stereogenic faces of an alkene; or two ormore prochiral moieties (e.g., related by symmetry in a prochiral ormeso molecule, (i.e., a molecule comprising at least two chiralcenters), both of which comprise an internal plane or point of symmetryor both. In general, catalysts intended by the present invention can becharacterized in terms of a number of features. For instance, a salientaspect of each of the catalysts contemplated by the instant inventionconcerns the use of asymmetric bicyclic or polycyclic scaffoldsincorporating the tertiary amine moiety which provide a rigid orsemi-rigid environment near the amine nitrogen. This feature, throughimposition of structural rigidity on the amine nitrogen in proximity toone or more asymmetric centers present in the scaffold, contributes tothe creation of a meaningful difference in the energies of thecorresponding diastereomeric transitions states for the overalltransformation. Furthermore, the choice of substituents may also effectcatalyst reactivity.

As mentioned above, the choice of catalyst substituents can also effectthe electronic properties of the catalyst. Substitution of the catalystwith electron-rich (electron-donating) moieties (for example, alkoxy oramino groups) may increase the electron density of the catalyst at thetertiary amine nitrogen, rendering it a stronger nucleophile and/orBronsted base and/or Lewis base. Conversely, substitution of thecatalyst with electron-poor moieties (for example, chloro ortrifluoromethyl groups) can result in lower electron density of thecatalyst at the tertiary amine nitrogen, rendering it a weakernucleophile and/or Bronsted base and/or Lewis base. To summarize thisconsideration, the electron density of the catalyst can be importantbecause the electron density at the tertiary amine nitrogen willinfluence the Lewis basicity of the nitrogen and its nucleophilicity.Choice of appropriate substituents thus makes possible the “tuning” ofthe reaction rate and the stereoselectivity of the reaction.

One aspect of the present invention relates to a compound represented byformula I:

wherein, independently for each occurrence:

R represents substituted or unsubstituted aralkyl or heteroaralkyl;

R₁ represents alkyl or alkenyl;

R₂ and R₃ represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl,heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy,amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine,carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether,ketone, aldehyde, or ester;

n is an integer from 0 to 5 inclusive;

m is an integer from 0 to 8 inclusive; and

R₄ represents OR₅, wherein R₅ is H or alkyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein R₅is H or CH₃.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein R₅is H.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Rrepresents aralkyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Rrepresents naphthalen-1-yl-methyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Rrepresents anthracene-9-yl-methyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein R₁is ethyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein R₁is —CH═CH₂.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein nis 0.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein mis 0.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris aralkyl and R₁ is alkyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris naphthalen-1-yl-methyl, and R₁ is ethyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris anthracene-9-yl-methyl, and R₁ is ethyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris aralkyl and R₁ is alkenyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris naphthalen-1-yl-methyl, and R₁ is —CH═CH₂.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris anthracene-9-yl-methyl, and R₁ is —CH═CH₂.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris aralkyl, R₁ is alkyl, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris naphthalen-1-yl-methyl, R₁ is ethyl, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris anthracene-9-yl-methyl, R₁ is ethyl, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris aralkyl, R₁ is alkenyl, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris naphthalen-1-yl-methyl, R₁ is —CH═CH₂, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris anthracene-9-yl-methyl, R₁ is —CH═CH₂, m is 0, and n is 0.

Another aspect of the present invention relates to a compoundrepresented by formula II:

wherein, independently for each occurrence:

R represents substituted or unsubstituted aralkyl or heteroaralkyl;

R₁ represents alkyl or alkenyl;

R₂ and R₃ represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl,heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy,amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine,carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether,ketone, aldehyde, or ester;

n is an integer from 0 to 5 inclusive;

m is an integer from 0 to 8 inclusive; and

R₄ represents OR₅, wherein R₅ is H or alkyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein R₅is H or CH₃.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein R₅is H.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Rrepresents aralkyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Rrepresents naphthalen-1-yl-methyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Rrepresents anthracene-9-yl-methyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein R₁is ethyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein R₁is —CH═CH₂.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein nis 0.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein mis 0.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris aralkyl and R₁ is alkyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris naphthalen-1-yl-methyl, and R₁ is ethyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris anthracene-9-yl-methyl, and R₁ is ethyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris aralkyl and R₁ is alkenyl.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris naphthalen-1-yl-methyl, and R₁ is —CH═CH₂.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris anthracene-9-yl-methyl, and R₁ is —CH═CH₂.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris aralkyl, R₁ is alkyl, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris naphthalen-1-yl-methyl, R₁ is ethyl, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris anthracene-9-yl-methyl, R₁ is ethyl, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris aralkyl, R₁ is alkenyl, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris naphthalen-1-yl-methyl, R₁ is —CH═CH₂, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned compound and any of the attendant definitions, wherein Ris anthracene-9-yl-methyl, R₁ is —CH═CH₂, m is 0, and n is 0.

Methods of the Invention—Catalyzed Reactions

In one aspect of the present invention there is provided a process forstereoselectively producing compounds with at least one stereogeniccenter from prochiral, or racemic starting materials. An advantage ofthis invention is that enantiomerically enriched products can besynthesized from prochiral or racemic reactants. Another advantage isthat yield losses associated with the production of an undesiredenantiomer can be substantially reduced or eliminated altogether.

In general, the invention features a stereoselective conjugate additionprocess which comprises combining a nucleophilic reactant, a prochiralor chiral substrate, and at least a catalytic amount of non-racemicchiral catalyst of particular characteristics (as described below). Thesubstrate of the reaction will include alkenes susceptible to attack bythe nucleophile. The combination is maintained under conditionsappropriate for the chiral catalyst to catalyze the conjugate additionbetween the nucleophilic reactant and alkene substrate. This reactioncan be applied to enantioselective processes as well asdiastereoselective processes. It may also be adapted for regioselectivereactions. Examples of enantioselective reactions, kinetic resolutions,and regioselective reactions which may be catalyzed according to thepresent invention follow.

The processes of this invention can provide optically active productswith very high stereoselectivity (e.g., enantioselectivity ordiastereoselectivity) or regioselectivity. In preferred embodiments ofthe subject desymmetrization reactions, products with enantiomericexcesses of greater than about 50%, greater than about 70%, greater thanabout 90%, and most preferably greater than about 95% can be obtained.The processes of this invention can also be carried out under reactionconditions suitable for commercial use, and typically proceed atreaction rates suitable for large scale operations.

As is clear from the above discussion, the chiral products produced bythe asymmetric synthesis processes of this invention can undergo furtherreaction(s) to afford desired derivatives thereof. Such permissiblederivatization reactions can be carried out in accordance withconventional procedures known in the art. For example, potentialderivatization reactions include the Nef reaction, the nucleophilicdisplacement, the reduction to amino group, the Myer reaction, theconversion into a nitrile oxide, and the like (Scheme 3).

The invention expressly contemplates the preparation of end-products andsynthetic intermediates which are useful for the preparation ordevelopment or both of therapeutic compounds.

One aspect of the present invention relates to a method of preparing achiral, non-racemic compound from a prochiral electron-deficient alkene,comprising the step of:

reacting a prochiral electron-deficient alkene with a nucleophile in thepresence of a catalyst; thereby producing a chiral, non-racemiccompound; wherein said catalyst is represented by formula I:

wherein, independently for each occurrence:

R represents substituted or unsubstituted aralkyl or heteroaralkyl;

R₁ represents alkyl or alkenyl;

R₂ and R₃ represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl,heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy,amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine,carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether,ketone, aldehyde, or ester;

n is an integer from 0 to 5 inclusive;

m is an integer from 0 to 8 inclusive; and

R₄ represents OR₅, wherein R₅ is H or alkyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R₅is H or CH₃.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R₅is H.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein Rrepresents aralkyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein Rrepresents naphthalen-1-yl-methyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein Rrepresents anthracene-9-yl-methyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R₁is ethyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R₁is —CH═CH₂.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein n is0.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein m is0.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isaralkyl and R₁ is alkyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isnaphthalen-1-yl-methyl, and R₁ is ethyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isanthracene-9-yl-methyl, and R₁ is ethyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isaralkyl and R₁ is alkenyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isnaphthalen-1-yl-methyl, and R₁ is —CH═CH₂.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isanthracene-9-yl-methyl and R₁ is —CH═CH₂.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isaralkyl, R₁ is alkyl, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isnaphthalen-1-yl-methyl, R₁ is ethyl, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isanthracene-9-yl-methyl, R₁ is ethyl, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isaralkyl, R₁ is alkenyl, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isnaphthalen-1-yl-methyl, R₁ is —CH═CH₂, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isanthracene-9-yl-methyl, R₁ is —CH═CH₂, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidnucleophile is a β-ketoester.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidnucleophile is a alkyl 2-cyano-2-arylacetate.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidprochiral electron-deficient alkene is a nitroalkene.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidprochiral electron-deficient alkene is an alkenyl sulfone.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidprochiral electron-deficient alkene is an alkenyl ketone.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidcatalyst is present in less than about 40 mol % relative to saidprochiral electron-deficient alkene.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidcatalyst is present in less than about 20 mol % relative to saidprochiral electron-deficient alkene.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidcatalyst is present in less than about 10 mol % relative to saidprochiral electron-deficient alkene.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidcatalyst is present in less than about 5 mol % relative to saidprochiral electron-deficient alkene.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidchrial non-racemic compound has an enantiomeric excess greater thanabout 70%.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidchrial non-racemic compound has an enantiomeric excess greater thanabout 90%.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidchrial non-racemic compound has an enantiomeric excess greater thanabout 95%.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isaralkyl; R1 is alkyl or alkenyl; and said nucleophile is a β-ketoester.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isnaphthalen-1-yl-methyl; R1 is ethyl; and said nucleophile is aβ-ketoester.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isanthracene-9-yl-methyl; R1 is ethyl; and said nucleophile is aβ-ketoester.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isaralkyl; R1 is alkyl or alkenyl; and said nucleophile is an alkyl2-cyano-2-aryl acetate.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isnaphthalen-1-yl-methyl; R1 is ethyl; and said nucleophile is an alkyl2-cyano-2-aryl acetate.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isanthracene-9-yl-methyl; R1 is ethyl; and said nucleophile is an alkyl2-cyano-2-aryl acetate.

Another aspect of the present invention relates to a method of preparinga chiral, non-racemic compound from a prochiral electron-deficientalkene, comprising the step of:

reacting a prochiral electron-deficient alkene with a nucleophile in thepresence of a catalyst; thereby producing a chiral, non-racemiccompound; wherein said catalyst is represented by formula II:

wherein, independently for each occurrence:

R represents substituted or unsubstituted aralkyl or heteroaralkyl;

R₁ represents alkyl or alkenyl;

R₂ and R₃ represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl,heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy,amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine,carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether,ketone, aldehyde, or ester;

n is an integer from 0 to 5 inclusive;

m is an integer from 0 to 8 inclusive; and

R₄ represents OR₅, wherein R₅ is H or alkyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R₅is H or CH₃.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R₅is H.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein Rrepresents aralkyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein Rrepresents naphthalen-1-yl-methyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein Rrepresents anthracene-9-yl-methyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R₁is ethyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R₁is —CH═CH₂.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein n is0.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein m is0.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isaralkyl and R₁ is alkyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isnaphthalen-1-yl-methyl, and R₁ is ethyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isanthracene-9-yl-methyl, and R₁ is ethyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isaralkyl and R₁ is alkenyl.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isnaphthalen-1-yl-methyl, and R₁ is —CH═CH₂.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isanthracene-9-yl-methyl, and R₁ is —CH═CH₂.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isaralkyl, R₁ is alkyl, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isnaphthalen-1-yl-methyl, R₁ is ethyl, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isanthracene-9-yl-methyl, R₁ is ethyl, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isaralkyl, R₁ is alkenyl, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isnaphthalen-1-yl-methyl, R₁ is —CH═CH₂, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isanthracene-9-yl-methyl, R₁ is —CH═CH₂, m is 0, and n is 0.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidnucleophile is a β-ketoester.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidnucleophile is a alkyl 2-cyano-2-arylacetate.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidprochiral electron-deficient alkene is a nitroalkene.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidprochiral electron-deficient alkene is an alkenyl sulfone.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidprochiral electron-deficient alkene is an alkenyl ketone.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidcatalyst is present in less than about 40 mol % relative to saidprochiral electron-deficient alkene.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidcatalyst is present in less than about 20 mol % relative to saidprochiral electron-deficient alkene.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidcatalyst is present in less than about 10 mol % relative to saidprochiral electron-deficient alkene.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidcatalyst is present in less than about 5 mol % relative to saidprochiral electron-deficient alkene.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidchrial non-racemic compound has an enantiomeric excess greater thanabout 70%.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidchrial non-racemic compound has an enantiomeric excess greater thanabout 90%.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein saidchrial non-racemic compound has an enantiomeric excess greater thanabout 95%.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isaralkyl; R1 is alkyl or alkenyl; and said nucleophile is a β-ketoester.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isnaphthalen-1-yl-methyl; R1 is ethyl; and said nucleophile is aβ-ketoester.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isanthracene-9-yl-methyl; R1 is ethyl; and said nucleophile is aβ-ketoester.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isaralkyl; R1 is alkyl or alkenyl; and said nucleophile is an alkyl2-cyano-2-aryl acetate.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isnaphthalen-1-yl-methyl; R1 is ethyl; and said nucleophile is an alkyl2-cyano-2-aryl acetate.

In certain embodiments, the present invention relates to theaforementioned method and any of the attendant definitions, wherein R isanthracene-9-yl-methyl; R1 is ethyl; and said nucleophile is an alkyl2-cyano-2-aryl acetate.

Nucleophiles

Nucleophiles which are useful in the present invention may be determinedby the skilled artisan according to several criteria. In general, asuitable nucleophile will have one or more of the followingproperties: 1) It will be capable of reaction with the substrate at thedesired electrophilic site; 2) It will yield a useful product uponreaction with the substrate; 3) It will not react with the substrate atfunctionalities other than the desired electrophilic site; 4) It willreact with the substrate at least partly through a mechanism catalyzedby the chiral catalyst; 5) It will not substantially undergo furtherundesired reaction after reacting with the substrate in the desiredsense; and 6) It will not substantially react with or degrade thecatalyst. It will be understood that while undesirable side reactions(such as catalyst degradation) may occur, the rates of such reactionscan be rendered slow—through the selection of reactants andconditions—in comparison with the rate of the desired reaction(s).

Nucleophiles which satisfy the above criteria can be chosen for eachsubstrate and will vary according to the substrate structure and thedesired product. Routine experimentation may be necessary to determinethe preferred nucleophile for a given transformation. For example, if anitrogen-containing nucleophile is desired, it may be selected fromammonia, phthalimide, hydrazine, an amine or the like. Similarly, oxygennucleophiles such as water, hydroxide, alcohols, alkoxides, siloxanes,carboxylates, or peroxides may be used to introduce oxygen; andmercaptans, thiolates, bisulfite, thiocyanate and the like may be usedto introduce a sulfur-containing moiety. Additional nucleophiles will beapparent to those of ordinary skill in the art. For nucleophiles whichexist as anions, the counterion can be any of a variety of conventionalcations, including alkali and alkaline earth metal cations and ammoniumcations. In certain embodiments, the nucleophile may be part of thesubstrate, thus resulting in an intramolecular reaction. The nucleophilemay be a primary (eq. 1), secondary (eq. 2), or tertiary (eq. 3)nucleophile as depicted below in Scheme 4.

Substrates

As discussed above, a wide variety of substrates are useful in themethods of the present invention. The choice of substrate will depend onfactors such as the nucleophile to be employed and the desired product,and an appropriate substrate will be apparent to the skilled artisan. Itwill be understood that the substrate preferably will not contain anyinterfering functionalities. In general, an appropriate substrate willcontain at least one reactive electrophilic center or moiety withdistinct stereogenic faces; or at least two electrophilic moietiesrelated by an internal plane or point of symmetry at which a nucleophilemay attack with the assistance of the catalyst. The catalyzed,stereoselective attack of the nucleophile at the electrophilic centerwill produce a chiral non-racemic product. Most of the substratescontemplated for use in the methods of the present invention contain atleast one double bond. The alkene in some embodiments will comprise anelectron withdrawing group making the double bond more susceptible tonucleophilic attack. Examples of suitable alkene substrates which aresusceptible to nucleophilic attack by the subject method includenitroalkenes, dialkyl azodicarboxylates, alkenyl sulfones, alkenylketones and the like.

In certain embodiments, the alkene is a prochiral or meso compound. Inother embodiments, the alkene will be a chiral compound. In certainembodiments, the substrate will be a racemic mixture. In certainembodiments, the substrate will be a mixture of diastereomers. Incertain embodiments, the methods of the present invention effect akinetic resolution. In certain embodiments, the methods of the presentinvention effect a dynamic kinetic resolution. In certain embodiments,the electron withdrawing group may be a nitro group, a sulfonyl, aketone, or a carboxylate.

Reaction Conditions

The asymmetric reactions of the present invention may be performed undera wide range of conditions, though it will be understood that thesolvents and temperature ranges recited herein are not limitative andonly correspond to a preferred mode of the process of the invention.

In general, it will be desirable that reactions are run using mildconditions which will not adversely effect the substrate, the catalyst,or the product. For example, the reaction temperature influences thespeed of the reaction, as well as the stability of the reactants,products, and catalyst. The reactions will usually be run attemperatures in the range of −78° C. to 100° C., more preferably in therange −20° C. to 50° C. and still more preferably in the range −20° C.to 25° C.

In general, the asymmetric synthesis reactions of the present inventionare carried out in a liquid reaction medium. The reactions may be runwithout addition of solvent. Alternatively, the reactions may be run inan inert solvent, preferably one in which the reaction ingredients,including the catalyst, are substantially soluble. Suitable solventsinclude ethers such as diethyl ether, 1,2-dimethoxyethane, diglyme,t-butyl methyl ether, tetrahydrofuran and the like; halogenated solventssuch as chloroform, dichloromethane, dichloroethane, chlorobenzene, andthe like; aliphatic or aromatic hydrocarbon solvents such as benzene,toluene, hexane, pentane and the like; esters and ketones such as ethylacetate, acetone, and 2-butanone; polar aprotic solvents such asacetonitrile, dimethylsulfoxide, dimethylformamide and the like; orcombinations of two or more solvents. Furthermore, in certainembodiments it may be advantageous to employ a solvent which is notinert to the substrate under the conditions employed, e.g., use ofethanol as a solvent when ethanol is the desired nucleophile. Inembodiments where water or hydroxide are not preferred nucleophiles, thereactions can be conducted under anhydrous conditions. In certainembodiments, ethereal solvents are preferred. In embodiments where wateror hydroxide are preferred nucleophiles, the reactions are run insolvent mixtures comprising an appropriate amount of water and/orhydroxide.

The invention also contemplates reaction in a biphasic mixture ofsolvents, in an emulsion or suspension, or reaction in a lipid vesicleor bilayer. In certain embodiments, it may be preferred to perform thecatalyzed reactions in the solid phase.

In some embodiments, the reaction may be carried out under an atmosphereof a reactive gas. For example, desymmetrization with cyanide asnucleophile may be performed under an atmosphere of HCN gas. The partialpressure of the reactive gas may be from 0.1 to 1000 atmospheres, morepreferably from 0.5 to 100 atm, and most preferably from about 1 toabout 10 atm.

In certain embodiments it is preferable to perform the reactions underan inert atmosphere of a gas such as nitrogen or argon.

The asymmetric synthesis processes of the present invention can beconducted in continuous, semi-continuous or batch fashion and mayinvolve a liquid recycle and/or gas recycle operation as desired. Theprocesses of this invention are preferably conducted in batch fashion.Likewise, the manner or order of addition of the reaction ingredients,catalyst and solvent are also not critical and may be accomplished inany conventional fashion.

The reaction can be conducted in a single reaction zone or in aplurality of reaction zones, in series or in parallel or it may beconducted batchwise or continuously in an elongated tubular zone orseries of such zones. The materials of construction employed should beinert to the starting materials during the reaction and the fabricationof the equipment should be able to withstand the reaction temperaturesand pressures. Means to introduce and/or adjust the quantity of startingmaterials or ingredients introduced batchwise or continuously into thereaction zone during the course of the reaction can be convenientlyutilized in the processes especially to maintain the desired molar ratioof the starting materials. The reaction steps may be effected by theincremental addition of one of the starting materials to the other.Also, the reaction steps can be combined by the joint addition of thestarting materials to the optically active metal-ligand complexcatalyst. When complete conversion is not desired or not obtainable, thestarting materials can be separated from the product and then recycledback into the reaction zone.

The processes may be conducted in either glass lined, stainless steel orsimilar type reaction equipment. The reaction zone may be fitted withone or more internal and/or external heat exchanger(s) in order tocontrol undue temperature fluctuations, or to prevent any possible“runaway” reaction temperatures.

Furthermore, the chiral catalyst can be immobilized or incorporated intoa polymer or other insoluble matrix by, for example, covalently linkingit to the polymer or solid support through one or more of itssubstituents. An immobilized catalyst may be easily recovered after thereaction, for instance, by filtration or centrifugation.

EXEMPLIFICATION

The invention now being generally described, it will be more readilyunderstood by reference to the following examples which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1 Preparation of DHQD-NAPM-OH and DHQD-ANTM-OH Catalysts

To a solution of dihydroquinidine (4.0 g, 12.4 mmol) in DMF (40 mL)under nitrogen atmosphere, NaH (1.36 g, 57% suspension in mineral oil,32.3 mmol) was added in small portions and the resulting mixture wasstirred at room temperature for 2 h. RC1 (13.6 mmol) was added dropwisevia a syringe over 10 min. The mixture was stirred at room temperatureovernight. After the starting material was completely consumed, brine(40 mL) was added carefully and the resulting mixture was extracted withethyl acetate (200 mL). The organic phase was washed with H₂O (5×100mL), brine (100 mL) and dried over Na₂SO₄. The solvent was removed invacuo to afford a light yellow oil. This crude product was used withoutfurther purification. Under N₂ atmosphere, a suspension of crude productand NaSEt (4.2 g, 50.0 mmol) in dry DMF (75 mL) was stirred at 110° C.for 9 hours. The reaction mixture was cooled to room temperature, andthe reaction was quenched with sat. NH₄Cl (80 mL) and H₂O (60 mL). Thesolution was acidified to pH=2 by addition of conc. HCl. This aqueoussolution was washed by ethyl acetate (2×100 mL) and its pH value wasadjusted to 8 by conc. ammonium hydroxide. The resulting mixture wasextracted with ethyl acetate (2×150 mL). The combined organic phase wasdried over Na₂SO₄, and concentrated in vacuo to afford a white solid.

NAPM-OH- and ANTM-OH-containing catalysts based on quinidine (QD),quinine (Q) and dihydroquinine (DHQ) may also be prepared in comparableyields using the procedure described in this Example. For example,Q-NAPM-OH may be prepared from Q as the starting material.

Example 2 Evaluation of Improved Catalysts DHQD-NAPM-OH and DHQD-ANTM-OH

The catalysts DHQD-NAPM-OH and DHQD-ANTM-OH were evaluated for theirefficiency as catalysts when compared to DHQD-PHN-OH in variousconjugate addition reactions.

General Procedure for Conjugate Additions with Various 6′-OH CinchonaAlkaloid Catalysts

A Michael donor was added to a solution of the Michael acceptor (14.7mg, 0.1 mmol) and 10 mol % catalyst in 0.2 mL organic solvent atspecified temperature. The reaction was monitored by either ¹H NMR (forcalculation of reaction conversion) or TLC (for indication of completereaction). The ee of the products was evaluated by HPLC equipped with achiral column following literature reported conditions.

When compared to DHQD-PHN-OH, catalysts DHQD-NAPM-OH and DHQD-ANTM-OHshowed significant improvement in the rate of the conjugate additionreactions as shown below. Interestingly, the catalysts showed comparableenantioselectivity.

Conjugate Addition of β-Ketoesters to Enones

Conjugate Addition of α-Cyanoacetates to Nitroolefins

Conjugate Additions of α-Cyanoacetates to Vinylsulfones

We claim:
 1. A compound represented by formula II:

wherein, independently for each occurrence: R represents substituted orunsubstituted aralkyl or heteroaralkyl; R₁ represents alkyl or alkenyl;R₂ and R₃ represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl,heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy,amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine,carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether,ketone, aldehyde, or ester; n is an integer from 0 to 5 inclusive; m isan integer from 0 to 8 inclusive; and R₄ represents OR₅, wherein R₅ is Hor alkyl.
 2. The compound of claim 1, wherein R represents aralkyl. 3.The compound of claim 1, wherein R represents naphthalen-1-yl-methyl. 4.The compound of claim 1, wherein R represents anthracene-9-yl-methyl. 5.The compound of claim 1, wherein R₅ is H.
 6. The compound of claim 1,wherein R represents naphthalen-1-yl-methyl; and R₅ is H.
 7. Thecompound of claim 1, wherein R represents anthracene-9-yl-methyl; and R₅is H.
 8. A method of preparing a chiral, non-racemic compound from aprochiral electron-deficient alkene, comprising the step of: reacting aprochiral electron-deficient alkene with a nucleophile in the presenceof a catalyst; thereby producing a chiral, non-racemic compound; whereinsaid catalyst is represented by formula II:

 wherein, independently for each occurrence: R represents substituted orunsubstituted aralkyl or heteroaralkyl; R₁ represents alkyl or alkenyl;R₂ and R₃ represent alkyl, alkenyl, aryl, cycloalkyl, aralkyl,heteroalkyl, halogen, hydroxy, cyano, amino, acyl, alkoxyl, silyloxy,amino, nitro, thiol, amine, imine, amide, phosphonate, phosphine,carbonyl, carboxyl, silyl, ether, thioether, sulfonyl, selenoether,ketone, aldehyde, or ester; n is an integer from 0 to 5 inclusive; m isan integer from 0 to 8 inclusive; and R₄ represents OR₅, wherein R₅ is Hor alkyl.
 9. The method of claim 8, wherein said nucleophile is aβ-ketoester.
 10. The method of claim 8, wherein said nucleophile is aalkyl 2-cyano-2-arylacetate.
 11. The method of claim 8, wherein saidprochiral electron-deficient alkene is a nitroalkene.
 12. The method ofclaim 8, wherein said prochiral electron-deficient alkene is an alkenylsulfone.
 13. The method of claim 8, wherein said prochiralelectron-deficient alkene is an alkenyl ketone.
 14. The method of claim8, wherein R represents aralkyl.
 15. The method of claim 8, wherein Rrepresents naphthalen-1-yl-methyl.
 16. The method of claim 8, wherein Rrepresents anthracene-9-yl-methyl.
 17. The method of claim 8, wherein R₅is H.
 18. The method of claim 8, wherein R representsnaphthalen-1-yl-methyl; and R₅ is H.
 19. The method of claim 8, whereinR represents anthracene-9-yl-methyl; and R₅ is H.